2-pyrazoline-1-carboxamide sulfonamide derivatives

ABSTRACT

2-PYRAZOLINE-1-CARBOXAMIDE SULFONAMIDE DERIVATIVES HAVING THE GENERAL FORMULA:   (3-R,4-R1,5-R2,5-R3-2-PYRAZOLIN-1-YL)-CO-NH-SO2-(1,4-   PHENYLENE)-Z   IN WHICH Z IS HYDROGEN, HALOGEN OR LOWER ALKYL, AND R, R1, R2, R3 ARE EACH HYDROGEN OR LOWER ALKYL. THESE SULFONAMIDE COMPOUNDS HAVE A HYPOGLYCEMIC EFFECT AND ARE OBTAINED BY REACTING A 2-PYRAZOLINE DERIVATIVES SUCH AS HN-CR2R3-CHR1-CR=N WITH AN ARYLSULFONYLUREA SUCH AS Z-C2H4EO2NHCONH2 OR WITH AN ARYLSULFONYLISOCYANATE SUCH AS Z-C6H4SO2NCO OR BY THE THERMAL DECOMPOSITION OF THE MOLECULAR COMBINATION OF THE 2PYRAZOLINE DERIVATIVE AND THE ARYSULFONYLUREA.

Dec. 1s, 1973 z. BRZOZOWSK. ml. 3,780,058

y ZPYRAZOLINE-l-CARBXAMIDE SULFONAMIDE DERIVATIVES Filed Sept. 16, 19715 Sheets-Sheet l R2 R1 I l R3-/C-CH z @Snam co-N\ FIG.l I

liz FIM R -c-cH N=CR FIG. 2

ZQSOZNHCONHZ FIG; 3

FIG. 4

Dec. 18, 1973 Az. BRZOZOWSKI UAL 3,780,058

2PYRAZOLINE 1 -CARBOXAMTDE SULFONAMIDE DERIVATIVES n 3 Sheets-Sheet 2Filed Sept. 16, 1971 Tomutumt v dose 10u mg/Kg Time {hours} 3,32@ N DEFIG. 5

Z8 [I Il m35@ DE@ Time (hours FlG.

AUnited States Patent O Int. c1. coi/d 49/10 U.S. Cl. 260-310 D 2 ClaimsABSTRACT F THE DISCLOSURE 2pyrazoline 1 carboxamide sulfonamidederivatives having the general formula:

in which Z is hydrogen, halogen or lower alkyl, and R, 25

R1, R2, R3 are each hydrogen or lower alkyl. These sulfonamide compoundshave a hypoglycemic eftect and are obtained by reacting a Z-pyrazolinederivative such as HN--CR2R3-CHR1-CR=N with an arylsulfonylurea such asZ-C6H4SO2NHCONH2 or with an arylsulfonyl- 30 isocyanate such asZ-C6H4SO2NCO or by the thermal decomposition of the molecularcombination of the 2- pyrazoline derivative and the arylsulfonylurea.

DRAWING In the lappended drawing: FIGS. 1-4 illustrate the structures ofcompounds relevant to the present invention; and 40 FIGS. -7 are graphsshowin-g the hypoglycemjc action of compounds according to the inventionin comparison with existing compounds.

31,780,058 Patented Dec. 18, 1973 ICC with N-arylsulfonylurea of thegeneral formula as given in FIG. 3, in the appended drawing, in which Zis of the meaning mentioned above, at a temperature of 80-130 C., in ananhydrous solvent, whose dielectric constant at a temperature of C. isless than 10 and whose boiling point is higher than 80 C. Such solventsare dioxane, chlorobenzene ctc. The compounds of the invention can alsobe obtained by heating the salts of such 2-pyrazoline derivatives suchas the salts of sulfuric acid etc.

-It is also possible to obtain the compounds if the molecularcombination of a suitable Z-pyrazoline derivative withN-arylsulfonylurea is subjected to thermal decomposition. Suchcombinations separate in the form of sparingly soluble deposits duringmixing of molar amounts of the components in the presence of -a solventhaving a low dielectric constant, such as, for instance, dioxane, at atemperature of 20-80o C.

It has been found that the N-arylsulfonylureas may be replaced byN-arylsulfonylisocyanates of the general formula as given in FIG. 4 inthe appended drawing, in which Z is of the meaning stated above, if thereaction with appropriate 2pyrazoline derivatives is conducted in inertsolvents or in solvents with which the N-arylsulfonylisocyanates formsimilarly reacting derivatives, such as, for instance, benzene,chlorobenzene, etc., initially aft a temperature of up to 20 C. and thenat a temperature of up to 80 C.

The compounds obtained according to said methods, are separated from thereaction mixture by dissolving them in aqueous hydroxide solutions, byextraction or by dissolving the remainder after distilling of thesolvent under reduced pressure, by separating the reaction byproductssparingly soluble in they alkaline medium, and by further precipitatingthem at slow neutralization or acidification of the solution diluted ina ratio of above 1:30 in relation to the mass of the product.

The compounds of the invention represent a new group of sulfonarnideshaving a strong hypoglycemic action and for this reason they can be usedfor the reduction of the glucose level in the blood. Some examples oftheir iniluence on the glucose level in the blood of rats, depending onthe action time of the orally administered 100 ang/kg. body weight doseare given in Table I.

TABLE I Ra Rz R1 Percent oi decrease or increase of the Z S O2NHC O--Nsugar concentration in the blood of rats (dose= 100 Ing/1 kg. of Weightof the rat), hours 0i N=CR measurement- Consecutive No. ofthe No.example Z R Ri Rr Rs 4 8 12 16 24 H CH; H H H H H H H CH3 H H 02H5 Hn-CaHy CHs H CH3 CH3 H H H H CH; H H H H H H CH3 H CzHs H n-CaH-l CH3 HCH3 CH3 H H H H H H H CH3 H 02H5 H 11-CaH7 CH3 H CH3 CH3 SUMMARY OF THEINVENTION The present invention relates to novel2-pyrazoline-lcarboxamide sulfonamide derivatives having the generalformula as given in FIG. 1, in the appended drawing, in which Z ishydrogen, la halogen or a lower alkyl group, and R, R1, R2 and R3 arehydrogen or a lower alkyl group.

Compounds according to the invention are obtained by heating appropriateZ-pyrazoline derivatives ofthe general formula as given in FIG. 2 in theappended drawing, in which R, R1, R2, R3 have the above-mentioned mcanmgWhen administering the SP-703 preparation and Tolbutamide to rats in adose of 100 mg./kg. of body weight, it is observed that the maximumhypoglycemic action of the two preparations occurs between the 4th and 8hour from the time of administration. However, the SP-703 preparationaction is still evident 24 hours after its introgastric administration.This difference is still more evident with a dose of 300 mg./kg. bodyweight where after 34 hours from the administration of the SP-703preparation, a substantial hypoglycemia is observed, whereas in the caseof Tolbutamide this action is maintained for about 20 hours only.

The influence of the SP-703 preparation dose on the sugar level in theblood has been examined and it was found that a maximum reduction of thesugar level in the blood is obtained after a dose of 400 mg./kg. bodyweight. A further increase in the dose of the preparation administereddoes not further lower the sugar level in the blood which reaches about40% of the Value before administration.

The toxic dose LD50 for mice after 24 hours from administration of theSP-703, given intragastrically, is 920 mg./kg., while for rats itexceeds 6 g./kg. When examining the toxicity during 7 days, it was foundthat females are more sensitive to the action of said preparation, andso the LD50 does for rat females was 620 mg./ kg., while for males itwas 1500 mg./ kg.

The gathered data is given in Table II.

4 control group was 24% and that of the group receiving 100 mg. and 300mg./kg. was about 20%.

For a better recognition of the operation mechanism of the SP-703preparation, examinations on rats aficted with heavy alloxan diabeteshave been made, but no influence of said preparation thereon has beenfound, nor was any influence found of Tolbutamide on the sugar level inthe blood. An oral glucose tolerance test has also been performed and isillustrated in Diagram 3, which shows a similar course of the SP-703preparation as compared to that for Tolbutamide.

This data indicates that the SP-703 preparation and Tolbutamide actthrough stimulation of insulin secretion, but it does not exclude thepossibility that the SP-703 preparation acts upon the gluconeogenesis orglucogenolysis process.

To resolve this, examination on underfed rats (containing no glycogen inthe liver) have been made. The administration of glucose, fructose andglycerol to such rats provides an increase of glycemia which becomesdistinctly decreased after the administration of the SP- 703preparation, whereas the obtained increase of glycogen in the liverremains without any change in spite of the administration of saidpreparation. No iniluence of the SP-703 preparation on the glycogenlevel in the muscles of well-fed and underfed rats has been observed.

This indicates the action of the SP-703 preparation through insulin.This is confirmed in tests in which the TABLE II Influence of SID-703 onsome morphologie and biochemical parameters in the blood of rats (7thday of administration) Kind of Mor- Glucose, Erythr., investitality, mg.Amylase, Ht, Hb, thousand] Leukooyt., gations percent percent GPT, IGOT, J .la/100 ml. percent g. percent mm.a llnun.l

Dose of the compound:

1.0 gramd' 0 53i10 95:5 385:5 1,0705:330 405:4 .75:1.8 4, 050:!:500 9,300:!:1,300 1.0 gram- Q 70 795:19 75:4 425:11 1, 2305:160 36i1 12. 35:1.2 4, 030:!:320 5, 3005:1, 900 0.3 gramo" 0 465:10 105:2 355:9 1,5105:270 415:2 13. 85:0. 9 4, 1305:330 8, 5005:2, 300 0.3 gram.. Q 10925:14 95:2 305:12 1, 510:!:220 395:3 13. 25:1. 2 4, 000:1:500 8,6005:2, 800 Control-- o 0 755:7 275:10 365:9 1, 7605:310 485:2 14. 7il.1 4, I4505:230 9, 400i1, 500 D0 Q 0 975:10 145:4 305:3 1, 420:!:250425:4 12. 85:0 7 4, 250:!:320 10, 3005:1, 000

Protracted toxicity examinations have been performed over a 10 monthperiod on mice, rats and rabbits, during which time the preparationunder examination was given in the food in two doses of 100 mg./ and 300mg./kg. body weight.

The average weight of the mice during the examination of protractedtoxicity of the SP-703 preparation is given in Table III below.

TABLE III Males Females Months Control gJkg. g./kg. Control g.kg gJkg.

No weight diiferences between the groups under examination and thecontrol group, as well as in the consumption of food and water have beenobserved.

Post mortem and histopathological examinations of the kidneys, liver,spleen, lungs and heart do not shown any changes in the two groups beingexamined. Biochemical examinations of the blood: diastase,aminotranspherase, GOT and GTP, haemoglobin, number of red bloodcorpuscles and also haemacrit, do not reveal differences between thecontrol group and the groups under examination.

No drop was observed in the number of white corpuscles in thecircumferential blood of mice examined as to protracted toxicity. Themortality 0f mice in the content of free fatty acids has been determinedand where it has been found that the SP-703 preparation distinctlydecreases the level of free fatty acids in the plasma of rats beingexamined.

Furthermore, it has been observed that the SP-703 preparation does notexert an influence on the glycogen level in the liver of underfed rats,but it considerably decreases the level in the liver of well-fed rats,which indicates an action that is contrary to the action of insulin andpresumes that the action of the SP-703 preparation is not connected withinsulin.

DESCRIPTION OF PARTICULAR EMBODIMENTS The method according to theinvention is more fully disclosed with reference to the followingexamples.

Example I 51.4 g. N-p-tolylsulfonylurea and 17 g. of Z-pyrazoline in 500ml. of dioxane are slowly heated to boiling and maintained thereat for 2hours. Then, under decreased pressure at a temperature of up to 60 C.the dioxane is distilled off and the remainder is dissolved in 1000 ml.of 1% aqueous ammonia solution. The solution obtained is neutralized toa pH=7 lby addition of hydrochloric acid, then it is decolorized withactive carbon and after dilution with 5000 ml. of water, it is slowlyacidiiied with 1% hydrochloric acid to pH=4. There are obtained 43 g. ofN-(p-tolylsulfonyl)-2-pyrazoline-l-carboxamide. Its melting point is164-165 C., and the yield 67.1%.

Example l1 To a solution of 17 g. of 2-pyrazoline in 1000 ml. ofchlorobenzene there is added dropwise at a temperature of 20 C., 11.8 g.of concentrated sulphuric acid, and then 51.4 g. ofN-p-tolylsulfonylurea is added and the mixture is heated for 4 hours ata temperature of 105- 110 C. After cooling, the reaction mixture issubjected to a triple extraction with a 2% aqueous ammonia solution,using each time 350 ml. of said solution. The subsequent procedure isaccording to Example I, and there is obtained 35 g. ofN-(p-tolylsulfonyl)-2-pyrazoline-1-carboxamide. The melting point is162.5-164.5 C. and the yield is 51%.

Example III To a solution of 14. g. of Z-pyrazoline in 200 ml. ofbenzene, a solution of 39.4 g. of p-tolylsulfonyl-isocyanate in 200 ml.of benzene is added so that the temperature does not exceed 40 C.,whereupon the mixture is heated for 1.5 hours at a temperature of 60 C.After cooling, the reaction mixture is subjected to a triple extractionby means of a 2% aqueous ammonia solution, using each time 300 ml. ofsaid solution. The joined extracts are diluted with water to a volume of3000 ml., then they are neutralized to a pH value of 7 by means ofhydrochloric acid and decolorized with active carbon. After separationofthe active carbon, 100 m1. of methyl alcohol are added to the filtrateand by slow acidication by addition of 1% hydrochloric acid to a pHvalue of 4 there is obtained 36.2 g. of N-(p-tolylsulfonyl)-2pyrazoline1carboxamide. The melting point is 16S-165 C.; the yield is 56.5%.

Example IV To a suspension of 107 g. of N-p-tolylsulfonylurea in 700 ml.of dioxane, 43.6 g. of S-methyl-Z-pyrazoline are added, the mixture isstirred for 1 hour at room temperature and then the whole mixture isslowly heated to boiling and maintained thereat for 4 hours. From theclear solution thus obtained, the dioxane is distilled off under reducedpressure at a temperature of up to 55 C. and the syrupy remainder isdissolved in 450 ml. of a 3% aqueous ammonia solution previously heatedto a temperature of 40 C. The solution obtained is diluted with 1500 ml.of water and at a temperature of 40 C. it is neutralized to a pH valueof 7-7.5 by addition of a 0.5% hydrochloric acid solution. The solutionis then decolorized by active carbon, and the reaction product isprecipitated by acidification with hydrochloric acid to a pH value of4.5, by the method stated below.

Into 1200 ml. of water, 5 g. of the product from the previous charge and100 ml. of the above obtained solution of the product, are introduced.Then, while continuously stirring, the 0.5% hydrochloric solution andfurther amounts of the solution of the precipitated product aresimultaneously very slowly introduced, the pH value of the mixture beingmaintained within the range of 5-6.

After the entire solution of the reaction product is added, theacidification is continued up to pH 4.5. There is obtained 128 g. ofS-methyl-N-(p-tolylsulfonyl-Z-pyrazoline-l-carboxamide. The meltingpoint is 11S-120 C., and the yield is 91%.

Example V 160 g. of N-p-tolylsulfonylurea and 68 g. of S-methyl-2-pyrazoline are successively introduced into 400 ml. of dioxane. Themixture is then stirred for 30 minutes at room temperature andsubsequently slowly heated to a temperature of up to 75-78 C., themixture being maintained at this temperature for l5 minutes. Aftercooling to a ternperature of C., stirring is continued for 3 hours,whereupon the precipitate is separated, and then dried at roomtemperature under reduced pressure. After heating the product at atemperature of 185 C. there is obtained 153 g. of a molecularcombination of N-p-tolylsulfonylurea with -methyl-2-pyrazoline having amelting point of 190 C.

Example VI 149.2 g. of the combination of N-p-tolylsulfonylurea With5-methyl-2-pyrazoline, obtained according to Example V is introducedinto 700 ml. of dioxane and heated for 2 hours at boiling. Afterseparation as described in Example IV, 131 g. of S-methyl-N-(p-tolylsulfonyl)-2-pyrazoline-l-carboxamide are obtained. 'Ihe meltingpoint is 119-121" C., the yield 93%.

Example VII 96.4 g. of N-p-tolylsulfonylurea and 40 g. of 5-methyl-Z-pyrazoline in 850 ml. of anhydrous toluene are stirred for 3 hours atroom temperature, whereupon the mixture is maintained at boiling up tocompletion of ammonia separation which takes about 12-15 hours. Aftercooling, the mixture is subjected to a quadruple extraction by means ofa 2% aqueous ammonia solution, using 200 m1. of said solution each time.

The joined extracts are decolorized with the aid of active carbon,whereupon they are diluted With 1000 ml. of water and then acidified byaddition of 0.5 hydrochloric acid to a pH value of 7.5. After a repeateddecolorization with active carbon, the reaction product is precipitatedby acidification to pH 4.5 using the method in EX- ample IV 115.9 g. ofS-methyl-N-(p-tolylsulfonyD-Z-pyrazoline-l-carboxamide 4are obtained.The melting point is 11S-120 C., and the yield 91.5%.

Example VIII To a solution of 19.7 g. of N-p-tolylsulfonylisocyanate in150 ml. of benzene, is added a solution of 8.4 g. of 5-methyl-Z-pyrazolne in 20 ml. of benzene so that the temperature does notexceed 30 C., whereupon the mixture is heated for 2 hours at atemperature of 60 C. After cooling, the mixture is subjected to a tripleextraction with a 25% aqueous ammonia solution, using 100 ml. of saidsolution each time. The joined extracts are heated to a temperature of40 C., whereupon they are neutralized to pH 7-7.5 by addition of 0.5%hydrochloric acid and then decolorized with active carbon. After theseparation of active carbon, the filtrate is added in portions to 500ml. of water containing a suspension of 2 g. of the product from theprevious charge and simultaneously 0.5% hydrochloric acid is addeddropwise so that the pH value is maintained within the range of 5-6.After the entire solution of the reaction product is added,acidification is continued up to a pH=4.5. 19.6 g. ofS-methyl-N-(ptolylsulfonyl)-2-pyrazoline-l-carboxamide are obtained. Themelting point is 118-120 C., and the yield is 69.7%.

Example IX 107.1 g. N-p-tolylsulfonylurea, 47 g. of 3methyl2- pyrazolinein 1000 rnl. of dioxane are heated for 3.5 hours at the boilingtemperature. The under reduced pressure at a temperature of 50 C., thedioxane is distilled off and the obtained crystal remainder is dissolvedin 1800 ml. of a 1% aqueous ammonia solution previously heated to atemperature of 40 C. 'Ille obtained solution is decolorized with activecarbon and after diluting with 600 ml. of water, the solution iscarefully acidied with 0.5 hydrochloric acid to a pH value of 6.5-7.After stirring for about 10-20 minutes, a crystal deposit begins to beprecipitated. Stirring is continued for 30 minutes, and thenacidification is continued to a pH value of 4.5-5. 128 g. of3-methyl-N-(p-tolylsulfonyl)-Z-pyrazoline 1 carboxamide are obtained.The melting point is 18S-190 C., and

' the yield is 91%.

Example X carbon, then diluted to a volume of 8000 ml. with water andafter heating to a temperature of 30-32 C. the solution is acidied with0.5% hydrochloric acid to pH 6. 74.1 g. of3,5,5-trimethyl-N-(p-tolylsulfonyl)-2-pyrazoline-l-carboxamide isobtained. The melting point is 164- 166 C. and the yield is 80%.

Example XI 107 g. of N-p-tolylsulfonylurea, and 70.1 g. of 4-ethyl-5-n-propyl-2-pyrazoline in 750 ml. of dioxane are heated for 4 hours atthe boiling temperature. Then under reduced pressure at a temperature ofup to 50 C. the dioxane is distilled off, 100 ml. of water is added andthen successive distilling is performed to remove the unreacted4-ethyl-5-n-propyl-2-pyrazoline.

The remainder is dissolved at a temperature of 40-50 C. in 1000 ml. of a2.5% aqueous ammonia solution, then ,it is decolorized with activecarbon, neutralized with hydrochloric acid to pH 8 and then decolorizedagain with active carbon. The colorless solution obtained is dilutedwith 6000 ml. of water and then acidied with 0.5% hydrochloric acid to apH value of 6.

16 g. of Z-ethyl-S-n-propyl-N-(p-tolylsulfonyl)-2-pyrazoline-l-carboxamide are obtained. The meltingpoint is 127-129 C. and the yield is 91%.

Example XII 100 g. of N-phenylsulfonylurea and 46 g. of 3-methyl-2-pyrazoline in 1000 ml. of dioxane are heated for 6 hours at theboiling temperature. After separation as described in Example IV, 119 g.S-methyl-N-(p-phenylsulfonyl)2 pyrazoline-l-carboxamide are obtained.The melting point is 14S-147 C., and the yield is 89%.

Example XIII 100 g. of N-phenylsulfonylurea and 43 g. of S-methyl-2-pyrazoline in 900 ml. of dioxane are slowly heated to boiling. In thisperiod N-phenylsulfonylurea is being dissolved, and shortly thereafterits molecular connection with S-methyl-Z-pyrazoline takes place, whichwhen further heated for 2.5 hours at boiling temperature, emits ammoniaand is converted toS-methyl-N-(phenylsulfonyl)-2-pyrazoline-l-carboxamide.

This compound is separated from the reaction mixture according to themethod as described in Example IX, its precipitation from the ammoniasolution being performed by acidification to pH 4. 52.8 g. of pureproduct are obtained. The melting point is 109-1l1 C. and the yield is39.5%.

Example XIV To a solution of 60 g. of N-phenylsulfonylurea in 700 ml. ofdoxane, 38.5 g. of 3,5,5-trimethyl-2-pyrazoline are added and themixture is heated to a temperature of 50 C. At this temperature thecrystal parent substance adduct (1:1) is precipitated which -whenfurther heated at the boiling temperature separates ammonia and isconverted to 3,5,5trimethyl-N-(phenylsulfonyl)-2-pyrazoline-l-carboxamide. After cooling,55.8 g. of pure crystal product are obtained from the reaction mixture.The melting point is 20S-211 C. and the yield is 63%.

Example XV The reaction of 3,5,5-trimethyl-2-pyrazoline with N-phenylsulfonylurea is carried out according to Example XIV, whereuponthe dioxane is distilled off under reduced pressure. The dry remainderis dissolved in 120 ml. of a 1% aqueous ammonia solution previouslyheated to a temperature of C. The solution obtained is neutralized bymeans of hydrochloric acid to a pH=8, whereupon the solution isdecolorized with active carbon and after dilution with water to a volumeof 5000 ml., the solution is acidied with 0.5% hydrochloric acid to a pHvalue of 7. 69.4 g. of 3,5,5-trimethyl-N-(phenylsulfonyl)2-pyrazoline-l-carboxamide are obtained. The melting point is 209-211 C.and the yield is 78.3%.

8 Example XVI 60 g. of N-phenylsulfonylurea and 40 g. of3,5,5-trimethyl-Z-pyrazoline in 1200 ml. of chlorobenzene are heated for5 hours at a temperature of 110 C. Then, under reduced pressure thechlorobenzene is distilled off and from the remainder 56 g. ofN-(benzenesulphonyl) 3,5,5-trimethyl-2-pyrazoline-l-carbonamide areobtained according to the method described in Example XIV. The meltingpoint is 208-210 C. and the yield is 63.2%.

Example XVII The method of Example XVI is effected with toluene insteadof chlorobenzene, 61.4 g. of 3,5,5-trimethyl-N-(phenylsulfonyl)-2-pyrazoline 1 carboxamide are obtained. The meltingpoint is 20S-210 C. andthe yield is 69.3%.

Example XVIII 70.5 g. of 4-ethyl-5-n-propyl-Z-pyrazoline, and 100 g. ofN-phenylsulfonylurea in 900 ml. of dioxane are heated to boiling. Acombination is obtained at a temperature of 70-75" C., and upon furtherheating for 2.5 hours at the boiling temperature, this is converted to4-ethyl-5-npropyl-N- (p-phenylsulfonyl) 2 pyrazoline 1 carboxamidepassing into the solution. From the reaction mixture the compound isisolated according to the method described in Example XI, itsprecipitation from the ammonium salt solution being performed byacidification to a pH value of 5.5. 152 g. of pure product are obtained.The melting point is 119-120 C. and the yield is 90.7%.

Example XIX To 500 ml. of dioxane, 56.3 g. of N-p-chlorophenylsulfonylurea and 17 g. of 2-pyrazoline are added, whereupon the reactionand the isolation of the product are carried out proceeding according toExample I, with the difference, however, that the precipitation of theproduct is performed with 0.5 hydrochloric acid to a pH value of 4.5. 51g. of N-(p-chlorophenylsulfonyl)-2-pyrazolinel-carboxamide are obtained.The melting point is 183- 185 C., and the yield is 73.9%.

Example XX To a solution of 13 g. of S-methyl-Z-pyrazoline in 400 ml. ofdioxane and ml. of toluene, 35 g. of N-pchlorophenylsulfonylurea areadded. The mixture is stirred for 2 hours at room temperature, whereuponthe mixture is boiled and maintained at rboiling up to completion of theammonia separation, which takes about 1.5-2 hours. From the reactionmixture thus obtained, the solvents are distilled off under reducedpressure (l0- 20 mm. Hg) while the remainder is dissolved in 300 ml. ofa 2% aqueous ammonia solution.

The solution obtained is diluted with 1800 ml. of water, neutralizedwith 0.5 hydrochloric acid to a pH value of 7-7.5, decolorized withactive carbon and then the reaction product is precipitated byacidication with hydrochloric acid to a pH value of 4.5. 41 g. of 5-methyl N (p chlorophenylsulfonyl) 2 pyrazolinel-carboxamide areobtained. The melting point is 113- 115 C. and the yield is 91.1%.

Example XXI To a solution of 22 g. of p-chlorophenylsulfonylisocyauatein 500 ml. of chlorobenzene, 9 g. of 5-methyl- 2-pyrazoline is addeddropwise so that the temperature does not exceed 20 C., then the entiresolution is slowly heated for 2 hours to a temperature of 80 C. which ismaintained for 15 minutes. After cooling, the reaction mixture issubjected to triple extraction by means of a 1% aqueous ammoniasolution, using each time 500 ml. of said solution.

The united extracts are decolorized by active carbon and then they areacidiiied with a 2% acetic acid solution to a pH value of 4.5. 23 g. of5methylN-(pchloro 9 phenylsulfonyl)-2-pyrazoline 1 carboxamide areobtained. The melting point is 113-115 C., and the yield is 69%.

Example XXII 70.4 g. of N-p-chlorophenylsulfonylurea and 38 g. of 3,5,5,trimethyl 2 pyrazoline in 750 ml. of dioxane are heated to boiling. At atemperature of about 40 C. the N-p-chlorophenylsulfonylurea becomesdissolved, and then at a temperature of 75-80 C. its molecularconnection with 3,5,5trimethy12pyrazoline (1:1) occurs, which uponfurther heating for two hours at the boiling temperature separatesammonia and becomes converted to 3,5,5 trimethylN-(p-chlorophenylsulfonyl) 2 pyrazoline-l-carboxamide. After separation,as described in Example XV, 83 g. of pure product are obtained. Themelting point is 15S-160 C. and the yield is 84%.

Example XXIII 117 g. of N p chlorophenylsulfonylurea and 71 g. of ethyl5 n propyl 2 pyrazoline in 800 ml. of dioxane are heated for 3 hours atthe -boiling temperature.

After separation as described in Example XI, 160 g. of 4 ethyl 5 npropyl N (chlorophenylsulfonyl)2 pyrazoline 1 carboxamide are obtained.The melting point is 107.5-110" C. and the yield is 89.4%. The crys- 2z-Q-sorNHoo-N 10 in which Z is hydrogen, halogen or lower alkyl, and R,R1, R2, R3 each is hydrogen or lower alkyl.

2. A compound as claimed in claim 1 Iwhich is 5- methyl-N-p-tolylsulfonyl) -Z-pyrazolinel-carboxamide.

References Cited UNITED STATES PATENTS 3,198,706 s/1965 Ruschig et a1.26o-553 D 3,384,757 5/1968 Ruschig etal. 26o-553 D FOREIGN PATENTS1,157,599 11/1963 Germany 26o-553 D 863,451 3/1961 Great Britain 26o-553D 896,303 5/1962 Great Britain 26o- 553 D OTHER REFERENCES Holland etal.: J. Med. Chem., vol. 3, pp. 99-110 1951).

Wiley et al.: Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles andCondensed Rings, pp. 241-6, New York, Interscience-Wiley, 1967.

Chemical Abstracts, vol. 68, Subject Index (P-Z), pp. 31905-31918(1968).

NATALIE TROUSOF, Primary Examiner U.S. Cl. X.R.

260--453 AR, 553 D, 553 DA; 424-273

